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Emerging Advances in Combinatorial Treatments of Epigenetically Altered Pediatric High-Grade H3K27M Gliomas

Somatic mutations in histone encoding genes result in gross alterations in the epigenetic landscape. Diffuse intrinsic pontine glioma (DIPG) is a pediatric high-grade glioma (pHGG) and one of the most challenging cancers to treat, with only 1% surviving for 5 years. Due to the location in the brains...

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Autores principales: Leszczynska, Katarzyna B., Jayaprakash, Chinchu, Kaminska, Bozena, Mieczkowski, Jakub
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503186/
https://www.ncbi.nlm.nih.gov/pubmed/34646308
http://dx.doi.org/10.3389/fgene.2021.742561
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author Leszczynska, Katarzyna B.
Jayaprakash, Chinchu
Kaminska, Bozena
Mieczkowski, Jakub
author_facet Leszczynska, Katarzyna B.
Jayaprakash, Chinchu
Kaminska, Bozena
Mieczkowski, Jakub
author_sort Leszczynska, Katarzyna B.
collection PubMed
description Somatic mutations in histone encoding genes result in gross alterations in the epigenetic landscape. Diffuse intrinsic pontine glioma (DIPG) is a pediatric high-grade glioma (pHGG) and one of the most challenging cancers to treat, with only 1% surviving for 5 years. Due to the location in the brainstem, DIPGs are difficult to resect and rapidly turn into a fatal disease. Over 80% of DIPGs confer mutations in genes coding for histone 3 variants (H3.3 or H3.1/H3.2), with lysine to methionine substitution at position 27 (H3K27M). This results in a global decrease in H3K27 trimethylation, increased H3K27 acetylation, and widespread oncogenic changes in gene expression. Epigenetic modifying drugs emerge as promising candidates to treat DIPG, with histone deacetylase (HDAC) inhibitors taking the lead in preclinical and clinical studies. However, some data show the evolving resistance of DIPGs to the most studied HDAC inhibitor panobinostat and highlight the need to further investigate its mechanism of action. A new forceful line of research explores the simultaneous use of multiple inhibitors that could target epigenetically induced changes in DIPG chromatin and enhance the anticancer response of single agents. In this review, we summarize the therapeutic approaches against H3K27M-expressing pHGGs focused on targeting epigenetic dysregulation and highlight promising combinatorial drug treatments. We assessed the effectiveness of the epigenetic drugs that are already in clinical trials in pHGGs. The constantly expanding understanding of the epigenetic vulnerabilities of H3K27M-expressing pHGGs provides new tumor-specific targets, opens new possibilities of therapy, and gives hope to find a cure for this deadly disease.
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spelling pubmed-85031862021-10-12 Emerging Advances in Combinatorial Treatments of Epigenetically Altered Pediatric High-Grade H3K27M Gliomas Leszczynska, Katarzyna B. Jayaprakash, Chinchu Kaminska, Bozena Mieczkowski, Jakub Front Genet Genetics Somatic mutations in histone encoding genes result in gross alterations in the epigenetic landscape. Diffuse intrinsic pontine glioma (DIPG) is a pediatric high-grade glioma (pHGG) and one of the most challenging cancers to treat, with only 1% surviving for 5 years. Due to the location in the brainstem, DIPGs are difficult to resect and rapidly turn into a fatal disease. Over 80% of DIPGs confer mutations in genes coding for histone 3 variants (H3.3 or H3.1/H3.2), with lysine to methionine substitution at position 27 (H3K27M). This results in a global decrease in H3K27 trimethylation, increased H3K27 acetylation, and widespread oncogenic changes in gene expression. Epigenetic modifying drugs emerge as promising candidates to treat DIPG, with histone deacetylase (HDAC) inhibitors taking the lead in preclinical and clinical studies. However, some data show the evolving resistance of DIPGs to the most studied HDAC inhibitor panobinostat and highlight the need to further investigate its mechanism of action. A new forceful line of research explores the simultaneous use of multiple inhibitors that could target epigenetically induced changes in DIPG chromatin and enhance the anticancer response of single agents. In this review, we summarize the therapeutic approaches against H3K27M-expressing pHGGs focused on targeting epigenetic dysregulation and highlight promising combinatorial drug treatments. We assessed the effectiveness of the epigenetic drugs that are already in clinical trials in pHGGs. The constantly expanding understanding of the epigenetic vulnerabilities of H3K27M-expressing pHGGs provides new tumor-specific targets, opens new possibilities of therapy, and gives hope to find a cure for this deadly disease. Frontiers Media S.A. 2021-09-27 /pmc/articles/PMC8503186/ /pubmed/34646308 http://dx.doi.org/10.3389/fgene.2021.742561 Text en Copyright © 2021 Leszczynska, Jayaprakash, Kaminska and Mieczkowski. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Leszczynska, Katarzyna B.
Jayaprakash, Chinchu
Kaminska, Bozena
Mieczkowski, Jakub
Emerging Advances in Combinatorial Treatments of Epigenetically Altered Pediatric High-Grade H3K27M Gliomas
title Emerging Advances in Combinatorial Treatments of Epigenetically Altered Pediatric High-Grade H3K27M Gliomas
title_full Emerging Advances in Combinatorial Treatments of Epigenetically Altered Pediatric High-Grade H3K27M Gliomas
title_fullStr Emerging Advances in Combinatorial Treatments of Epigenetically Altered Pediatric High-Grade H3K27M Gliomas
title_full_unstemmed Emerging Advances in Combinatorial Treatments of Epigenetically Altered Pediatric High-Grade H3K27M Gliomas
title_short Emerging Advances in Combinatorial Treatments of Epigenetically Altered Pediatric High-Grade H3K27M Gliomas
title_sort emerging advances in combinatorial treatments of epigenetically altered pediatric high-grade h3k27m gliomas
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503186/
https://www.ncbi.nlm.nih.gov/pubmed/34646308
http://dx.doi.org/10.3389/fgene.2021.742561
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